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After the serendipitous discovery of the first antidepressants, for years the only pharmacodynamic mechanisms explored in the search of novel antidepressants were those related to the 3 main monoamines: serotonin, norepinephrine, and dopamine. New-generation monoaminergic antidepressants, such as selective-serotonin and dual-acting serotonin\/norepinephrine reuptake inhibitors, improved treatment and quality of life of depressed patients. Nevertheless, there are still important clinical limitations: the long latency of onset of the antidepressant action; side effects, which can lead to early discontinuation; low rate of response; and high rate of relapse\/recurrence. Therefore, in the last several years, the focus of research has moved from monoamines toward other molecular mechanisms, including glutamatergic (Glu) neurotransmission. This review provides a comprehensive overview of the current knowledge on the Glu system and on its relationships with mood disorders. Up to now, N-methyl-D-aspartate (NMDA) receptor antagonists, in particular ketamine, provided the most promising results in preclinical studies and produced a consistent and rapid, although transient, antidepressant effect with a good tolerability profile in humans. Although data are encouraging, more double-blind, randomized, placebo-controlled trials are needed to clarify the real potentiality of ketamine, and of the other Glu modulators, in the treatment of unipolar and bipolar depression.<\/jats:p>","DOI":"10.1017\/s1092852912000971","type":"journal-article","created":{"date-parts":[[2013,2,1]],"date-time":"2013-02-01T16:09:06Z","timestamp":1359734946000},"page":"188-198","source":"Crossref","is-referenced-by-count":20,"title":["Glutamate system as target for development of novel antidepressants"],"prefix":"10.1017","volume":"18","author":[{"given":"Mario","family":"Catena-Dell'Osso","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Fagiolini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Rotella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Baroni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donatella","family":"Marazziti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"56","published-online":{"date-parts":[[2013,2,1]]},"reference":[{"key":"S1092852912000971_ref90","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2007.05.028"},{"key":"S1092852912000971_ref88","doi-asserted-by":"publisher","DOI":"10.1176\/jnp.2010.22.4.442"},{"key":"S1092852912000971_ref32","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.61.7.705"},{"key":"S1092852912000971_ref64","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2003.10.009"},{"key":"S1092852912000971_ref58","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2011.02.024"},{"key":"S1092852912000971_ref86","doi-asserted-by":"publisher","DOI":"10.1126\/science.1222939"},{"key":"S1092852912000971_ref91","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2011.03.019"},{"key":"S1092852912000971_ref84","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2004.11.023"},{"key":"S1092852912000971_ref77","doi-asserted-by":"publisher","DOI":"10.1097\/YCT.0b013e3181c3b0aa"},{"key":"S1092852912000971_ref2","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.9078tx1c"},{"key":"S1092852912000971_ref83","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2004.03.013"},{"key":"S1092852912000971_ref80","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.163.1.153"},{"key":"S1092852912000971_ref75","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2012.12020219"},{"key":"S1092852912000971_ref63","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.01.073"},{"key":"S1092852912000971_ref71","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2009.08.038"},{"key":"S1092852912000971_ref59","article-title":"The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine","author":"Monteggia","journal-title":"Biol Psychiatry."},{"key":"S1092852912000971_ref5","unstructured":"World Health Organization. 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